Microglial FKBP51 drives immunometabolic dysfunction linking perioperative neurocognitive disorders and Alzheimer's disease.

BACKGROUND: Perioperative neurocognitive disorders (PND) and Alzheimer's disease (AD) are both important aging related cognitive disorders. Accumulating evidence suggests that they share common pathological mechanisms involving Aβ deposition, neuroinflammation, and immunometabolic imbalance. However, the key regulatory molecules linking these two conditions remain unclear. FKBP prolyl isomerase 51 (FKBP51) is an immune regulatory molecule widely involved in inflammation control and metabolic homeostasis maintenance, but its role in PND and AD is still unknown. This study aimed to investigate whether FKBP51 participates in the shared pathological processes of PND and AD by regulating microglial immunometabolism. METHODS: This study integrated transcriptomic data from PND and AD brain tissues to screen for commonly abnormally expressed metabolism related genes and analyzed key hub genes in relation to clinical cognitive scores. The Brain RNA-seq database, single cell RNA sequencing data, and immunofluorescence staining were used to determine the cellular localization and expression characteristics of FKBP51. Primary microglia were stimulated with oligomeric Aβ42, and Fkbp5 expression was knocked down using siRNA to evaluate its effects on microglial inflammatory responses and Aβ phagocytosis. Furthermore, single gene GSEA, Seahorse metabolic analysis, and ROS and JC-1 detection were combined to investigate the regulatory role of FKBP51 on microglial mitochondrial function and oxidative phosphorylation. RESULTS: Bioinformatics analysis identified FKBP51 as a key metabolism related hub gene that was commonly abnormally elevated in both PND and AD brain tissues, and its expression level was significantly correlated with cognitive decline in AD patients. Further studies revealed that FKBP51 was enriched in microglia and was significantly upregulated in brain tissues from AD patients and model mice. Aβ42 stimulation markedly induced FKBP51 expression in microglia. Functional experiments demonstrated that Fkbp5 knockdown enhanced microglial phagocytic capacity for Aβ and reduced the expression and secretion of proinflammatory factors. Mechanistic studies showed that FKBP51 was closely associated with pathways related to fatty acid oxidation and oxidative phosphorylation. Following FKBP51 inhibition, maximal respiration capacity and ATP production in microglia were significantly increased, mitochondrial membrane potential was improved, and ROS accumulation was markedly reduced. These metabolic improvements were accompanied by restoration of microglial phagocytic function and alleviation of the inflammatory state. CONCLUSIONS: This study reveals that FKBP51 is an important immunometabolic regulatory molecule linking the shared pathological processes of PND and AD. Abnormal upregulation of FKBP51 promotes microglial functional imbalance by inhibiting mitochondrial oxidative phosphorylation and inducing oxidative stress, thereby exacerbating Aβ related neuroinflammation and cognitive impairment. Targeting FKBP51 mediated microglial metabolic reprogramming may provide a novel intervention strategy for aging related cognitive disorders such as PND and AD.